This is the Phase 1 application of an SBIR proposal entitled "Novel Inhibitors for the Treatment of Highly Drug Resistant Chronic Myelogenous Leukemia." The overall goal of this proposal is to test the efficacy of a class of novel small molecule scaffolds, which have been discovered and developed by HPRL, in a mouse model of leukemia. A secondary goal is to further optimize two or three of the best lead candidates for cellular specificity and oral bioavailability. All of the HPRL compounds relevant to this proposal are nanomolar inhibitors of the T315I mutant of the BCR-ABL oncogene product, an oncoprotein which is of central importance in the develompent of chronic myelogenous leukemia (CML). The NIH support will be used to focus research at Housey Pharmaceutical Research Laboratories (hereinafter "HPRL") to further develop and commercialize discoveries originally made in the laboratories of Dr. Charles Sawyers, M.D., at the University of California at Los Angeles (UCLA), Los Angeles, CA, which have been exclusively licensed to HPRL for therapeutic applications. This Phase I proposal builds upon the solid scientific foundation established by Dr. Sawyers and his colleagues while at UCLA. Dr. Sawyers is now the Chairman of the Human Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center and serves as HPRL's Principal Scientific Advisory Board member and Senior Consultant with respect to this therapeutic program. Over the past eight years Dr. Sawyers and his colleagues, including Dr. Neil Shah, M.D. (now at UCSF), have made seminal discoveries surrounding the development of resistance to imatinib mesylate (Gleevec), a medicine which has revolutionized the treatment of chronic myelogenous leukemia (CML). They have also made key contributions to the development of dasatinib (Sprycel), a compound which is capable of treating some, but not all, of the BCR-ABL mutations that emerge in CML patients who eventually develop imatinib resistance. The proposal provides the unique opportunity to further develop and commercialize key intellectual property and technology originally created by NIH-supported scientists at the University of California at Los Angeles (UCLA), the Memorial Sloan Kettering Cancer Center (MSKCC), and the University of California at San Francisco (UCSF) who are acknowledged leaders in the field. The proposal brings together the academic expertise of leaders in the field of imatinib resistance with Housey Pharmaceutical Research Laboratories (HPRL), an organization whose scientists have a strong track record of creating, developing and commercializing intellectual property and technology of formidable market value. Cell-based assay technology originally developed by Housey scientists has been licensed and is in use at the majority of the world's best research-driven pharmaceutical concerns. PUBLIC HEALTH RELEVANCE: Development of novel therapeutic agents for the treatment of drug-resistant chronic myelogenous leukemia and other forms of cancer.